Editor’s Note
	An Important New Treatment Option Becomes Available.

The lead interview for this issue of Colorectal Cancer Update focuses on one of the most exciting new data sets in the field for many years. Richard Goldberg’s ASCO presentation in Orlando this May surprised many observers by demonstrating a progression-free and overall survival advantage for the so-called FOLFOX regimen compared to the Saltz regimen and to a combination of oxaliplatin and irinotecan.

Oxaliplatin has just been approved by the FDA for use in combination with infusional 5-FU and leucovorin in patients who have progressed after receiving irinotecan and bolus 5-FU/leucovorin. The approval time of seven weeks is the shortest ever for a cancer drug in this country. It must be noted that oxaliplatin is also frequently associated with neurotoxicity, which seems acceptable in the metastatic setting but may be more problematic as adjuvant therapy.

Dr Goldberg notes that from a scientific perspective, the survival data in this new report are challenging to interpret, because patients randomized to irinotecan/ 5-FU/leucovorin (IFL) generally did not have the opportunity to receive oxaliplatin on progression, while those randomized to FOLFOX were able to receive irinotecan. Perhaps the key conclusion is that the availability of oxaliplatin, irinotecan and some variation of 5-FU is improving the prognosis for metastatic colorectal cancer, and that these advances are likely to have even more impact in the adjuvant setting.

A recurring theme in my recent interviews with colorectal cancer research leaders is that pharmacologic interventions have taken a giant step forward in the last 5-10 years, and practicing oncologists now have available far more options both in the protocol and nonprotocol setting. In addition to developing agents and regimens with greater antitumor activity, current trials are also attempting to develop therapies with fewer side effects and toxicities.

One point of great interest in the FOLFOX presentation at ASCO was that the regimen included infusional 5-FU, which causes more patient inconvenience than bolus therapy. However, speakers interviewed for this program report encouraging phase II trials utilizing capecitabine combinations in lieu of infusional 5-FU. Chris Twelves discusses his work on capecitabine/oxaliplatin, which by indirect comparison seems comparable in efficacy to the FOLFOX regimen and will likely now move into phase III randomized trials.

David Kerr reviews another encouraging data set attempting to substitute capecitabine for 5-FU, specifically in combination with irinotecan. Combinations of capecitabine with either irinotecan or oxaliplatin are considered experimental, and these regimens should not currently be utilized in the nonprotocol setting. As commented on by John Marshall in the inaugural issue of Colorectal Cancer Update, the key dose-limiting toxicity of capecitabine is hand-foot syndrome, and while this side effect can be minimized with careful attention to dosing and patient education, the ASCO meeting included another presentation that offers an alternative approach to this problem.

Edward Lin performed a retrospective case-controlled study of colorectal cancer patients receiving capecitabine who were also receiving the COX-2 inhibitor, celecoxib, for comorbid conditions. Dr Lin theorized that the hand-foot syndrome and perhaps diarrhea associated with capecitabine might be mediated through COX-2, and his new data set provides encouraging pilot data suggesting that celecoxib might be useful in preventing or treating these side effects. Again, further research is required before this strategy should be used outside a research setting.

The recent explosion of clinical trial data in colorectal cancer typified by the ASCO meeting also brings to mind the complexities of translating exciting new advances like the FOLFOX data into patient care. I asked Alan Venook to select a patient from his practice who typified this challenge, and he described a patient with the fascinating initial presentation of infected liver metastases. When this young man was stable enough to receive systemic antitumor therapy, a misjudgement in clinical assessment almost had disastrous repercussions.

Specifically, Dr Venook notes that a key predictive factor for toxicity from trials of the IFL regimen has been performance status, and that frightened patients have a tendency to obfuscate their daily difficulties. In this case, in spite of Dr Venook’s suspicions that his patient was doing much more poorly than it appeared in the clinic, the IFL regimen was utilized as part of a phase II study evaluating an angiogenesis inhibitor. The patient’s performance status rapidly deteriorated, he was removed from the study and switched to a less toxic treatment. Dr Venook notes the important lesson from this case is that efficacy and tolerability data reported from clinical trials must be carefully studied by practitioners before implementing the treatment into nonprotocol care. In particular, he cautions that patients recruited for studies may be younger and in better overall health than those in day-to-day community practice.

Dr Venook’s case is an important reminder of the challenge of translating clinical research into patient care, which is the major focus of our educational series. Through 14 years of utilizing the one-on-one interview format, we have learned to pose the difficult questions to investigators for which practicing oncologists seek answers. All of us like to remember the patients who responded well to our therapeutic recommendations, but research “mavens” like Alan Venook also have enough clinical experience to know the pitfalls of incorporating new therapies into patient care.

Those of us who entered oncology before 1990 remember the dreary and very small list of therapeutic options for colorectal cancer treatment, and chemoprevention was rarely even discussed. Today, we now have entered a new era in the field, and it seems likely that a multipronged research approach combining new strategies for prevention, early detection and systemic treatment may result in a significant impact on the morbidity and mortality of this very common disease.

— Neil Love, MD

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